Hydrates of optionally substituted 2-(2-pyridinyl) methylthio-1H-benzimidazoles and process for the production thereof

ABSTRACT

The invention relates to crystals from optionally substituted 2-(2-pyridinyl)methylthio-1H-benzimidazole hydrates and to a method for the production thereof.

This application is a division of U.S. patent application Ser. No.10/772,033 filed Feb. 4, 2004, now U.S. Pat. No. 7,435,825, which is acontinuation of PCT/EP02/08867 filed Aug. 8, 2002, which claims priorityof DE 101 40 492. 1 filed Aug. 17, 2001.

The invention relates to crystals of optionally substituted2-(2-pyridinyl)methylthio-1H-benzimidazole hydrates and to a process forthe production thereof.

It is known that 2-(2-pyridinyl)methylthio-1H-benzimidazole compounds,such as for example pyrmetazole(5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylthio]-1H-benzimidazole)are the final intermediate for the production of antiulceratives, inparticular omeprazole or lanzoprazole. Such an antiulcerative isproduced by converting the sulfide compound, such as for examplepyrmetazole, by oxidation into the corresponding sulfinyl compound, suchas for example omeprazole.

Substituted 2-(2-pyridinyl)methylthio-1H-benzimidazoles areconventionally produced under alkaline conditions in organic solvents byreaction of mercaptobenzimidazole compounds, such as for example5-methoxy-2-mercapto-benzimidazole, with reactive pyridine compounds,such as for example 2-chloromethyl-3,5-dimethyl-4-methoxypyridine.

EP 0 005 129 A describes the production of2-(2-pyridinyl)methylthio-1H-benzimidazole compounds by reactingsuitable mercaptobenzimidazole compounds with chloromethylpyridinecompounds. The reaction proceeds in an organic solvent, such as forexample ethanol, in the presence of a base, such as for example sodiumhydroxide.

Once the reaction is complete, the resultant common salt is separated,the solvent removed under a vacuum and the monohydrochloride of thecompound is caused to crystallise by means of concentrated hydrochloricacid in acetone and is purified. The yields achieved in this process arebarely satisfactory. Moreover, the hydrochloride must be converted backinto the base before the oxidation reaction.

EP 0 074 341 A describes the production of2-(2-pyridinyl)-methylthio-1H-benzimidazole compounds by reactingsuitable mercaptobenzimidazole compounds with chloromethylpyridinecompounds in the presence of sodium hydroxide. Methanol is used as thesolvent. Once the reaction is complete and water has been added, the2-(2-pyridinyl)methylthio-1H-benzimidazole compound is purified byrepeated extraction with methylene chloride and recrystallisation fromacetonitrile. The solvents used in this process are hazardous to theenvironment. Moreover, due to the repeated extraction steps, the processis time-consuming.

EP 0 899 268 A2 describes inter alia the production of2-[2-(4-chloro-3,5-dimethylpyridyl)methylthio]-5-methoxy-1H-benzimidazoleby the reaction of suitable starting compounds in tetrahydrofuran and inthe presence of sodium hydroxide solution. Once the reaction is completeand water has been added, the stated compound is isolated by repeatedextraction with methylene chloride and evaporation of the solvent. Thecompound is obtained as a viscous oil. Disadvantageous features of thisprocess are the use of a solvent which is hazardous to the environmentand the time-consuming isolation by repeated extraction. Moreover, theproduct in the form of a viscous oil is more technically demanding tohandle than a crystalline compound.

The object of the present invention was accordingly to provide theoptionally substituted 2-(2-pyridinyl)-methylthio-1H-benzimidazoles in aform which is stable and can be stored and is obtained bystraightforward processing steps in elevated yields and in high purity,wherein it is possible to use solvents which are more environmentallyfriendly and present a reduced hazard to health.

The object is achieved by the provision of crystals of optionallysubstituted 2-(2-pyridinyl)methylthio-1H-benzimidazole hydrates of thestructural formula I,

in which

-   R¹, R² and R³, identical or different, denote hydrogen, C1-C8 alkyl,    C3-C8 cycloalkyl, C2-C8 fluoroalkyl or C1-C8 alkoxy,-   R⁴ and R⁵, identical or different, denote hydrogen, C1-C8 alkyl,    C3-C8 cycloalkyl, CH₂—C3-C8 cycloalkyl, C1-C8 alkoxycarbonyl, C1-C8    alkoxy, C1-C8 fluoroalkoxy, CF₃, C2-C8 fluoroalkyl or —C(O)O—C1-C8    alkyl and-   R⁶, identical or different, denotes hydrogen or C1-C2 alkyl and-   x denotes 0.5-2.-   R¹-R⁶ preferably have the following meaning-   R¹, R² and R³, identical or different, denote hydrogen, C1-C3 alkyl    or C1-C3 alkoxy,-   R⁴ and R⁵, identical or different, denote hydrogen, C1-C3 alkoxy,    C1-C3 fluoroalkoxy and-   R⁶, identical or different, denotes hydrogen.

Particularly preferred compounds are those in which R¹ denotes a methylgroup, R² a methoxy group, R³ a methyl group, R⁴ hydrogen, R⁵ a methoxygroup in position 5 and R⁶ hydrogen or

in which R¹ denotes hydrogen, R² and R³ in each case denote a methoxygroup, R⁴ denotes hydrogen, R⁵ a difluoromethoxy group in position 5 andR⁶ hydrogen.

The present invention also provides a process for the isolation of acompound according to formula I from a reaction medium, in which thecompound is present as a free base, in elevated yields, wherein awater-miscible, organic solvent present in the reaction medium is atmost partially removed and water is added to the reaction medium at atemperature of below 40° C., preferably of 20-25° C., in quantities ofat least 55 wt. %, preferably at least 70 wt. %, particularly preferablyup to 75 wt. %, relative to the reaction medium, and the consequentlyformed hydrates are separated as crystals and optionally purified inconventional manner and dried. When removing the organic solvent, careshould be taken to ensure that its concentration does not fall below thesolubility limit for the compound of the formula I.

The compounds of the formula I are preferably to be separated from areaction medium which is obtained by reacting a thiol compound of theformula II

in which R⁴ and R⁵ have the above-stated meaning, with a reactivepyridine compound of the formula III,

in which R¹, R², R³ and R⁶ have the above-stated meaning, in awater-miscible, organic solvent in the presence of a base. Suitablebases for this reaction are preferably sodium and/or potassiumhydroxide. This reaction preferably proceeds with several hours'refluxing. The reaction may be performed continuously ordiscontinuously.

The compound of the formula I may be obtained from the reaction medium,which contains the compound as a free base, by at most partial removalof the water-miscible, organic solvent and by addition of water inquantities of at least 55 wt. %, preferably at least 70 wt. %,particularly preferably up to 75 wt. %, relative to the reaction medium,at a temperature of below 40° C., preferably of 20-25° C. When removingthe organic solvent, care should be taken to ensure that itsconcentration does not fall below the solubility limit for the compoundof the formula I.

The sodium and/or potassium chloride arising from the neutralisation ofthe added base may be separated beforehand by suitable means, forexample by filtration, or be dissolved by the addition of water onformation of the hydrate. The hydrates of the2-(2-pyridinyl)methylthio-1H-benzimidazoles may optionally be furtherpurified and dried.

Thiol compounds of the formula II may be purchased commercially.Reference is also made to EP 0 254 588, EP 0 005 129 and EP 0 074 341for a description of the synthesis thereof, the correspondingdescription hereby being introduced as part of the present disclosure.Reference is made to WO 98/50361 and WO 97/29103 for a description ofthe synthesis of the reactive pyridine compounds of the formula III, thecorresponding description hereby being introduced as part of the presentdisclosure.

The present invention also provides a process for the production of acompound according to the formula I, in which the unhydrated compound ofthe formula I is dissolved in a water-miscible, organic solvent orsolvent mixture and is caused to crystallise by addition of water inquantities of at least 55 wt. %, preferably at least 70 wt. %,particularly preferably up to 75 wt. %, relative to the reaction medium,at a temperature of below 40° C., preferably of 20-25° C., and theconsequently formed crystals of the compound according to the formula Iare separated, optionally purified and dried.

The water-miscible, organic solvents used in the above-stated reactionsare preferably highly volatile solvents, such as aliphatic alcohols,aprotic solvents or ketones, particularly preferably methanol, ethanol,propanol, butanol, dimethylformamide, dimethyl sulfoxide,tetrahydrofuran or acetone, or mixtures of at least two of thesesolvents.

The present invention also provides a process for the purification ofcrystals of a compound according to the formula I, in accordance withwhich the hydrate to be purified is washed at least once with waterand/or a solvent/water mixture, preferably an alcohol/water mixtureand/or a ketone/water mixture, and is then dried under a vacuum at belowthe melting point of the hydrates.

The crystals according to the invention of the optionally substituted2-(2-pyridinyl)methylthio-1H-benzimidazole hydrates of the formula I arestable and can be stored. They are straightforward to produce, isolateand purify and may be used directly for oxidation to yield thecorresponding sulfinyl compounds, which are used as an antiulcerative.With the assistance of the process according to the invention, it ispossible to produce crystals of optionally substituted2-(2-pyridinyl)-methylthio-1H-benzimidazole hydrates of the formula I inelevated yields and in high purity, wherein it is possible to usesolvents which are more environmentally friendly and present a reducedhazard to health.

The following Examples illustrate the invention without limiting itthereto.

EXAMPLES Example 1

0.05 mol of 2-mercapto-5-methoxybenzimidazole were added to a solutionof 0.11 mol of sodium hydroxide in 90 ml of ethanol. 0.05 mol of2-chloromethyl-3,5-dimethyl-4-methoxy-pyridine hydrochloride were addedto the solution and the reaction mixture was refluxed for 14 hours. 270ml of water were then added at room temperature (25° C.), wherein thehydrates of5-methoxy-2-[3,5-dimethyl-4-methoxypyridinyl)-methylthio]-1H-benzimidazolecrystallised. The whitish crystalline product was separated, washed withwater and dried under a vacuum.

Yield: 95% relative to theoretical yield (15.6 g).

The purity of the compound was determined by HPLC and was 99.7%.

Example 2

0.1 mol of 2-mercapto-5-methoxybenzimidazole were added to a solution of0.22 mol of sodium hydroxide in 250 ml of methanol. 0.1 mol of2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride were addedto the solution and the reaction mixture was refluxed for 16 hours. 80ml of solvent were then removed under a vacuum and 400 ml of water werethen added at room temperature (25° C.), wherein the hydrates of5-methoxy-2-[3,5-dimethyl-4-methoxy-pyridinyl)methylthio]-1H-benzimidazolecrystallised. The whitish crystalline product was separated, washed withmethanol/water and dried under a vacuum.

Yield: 92.5% relative to theoretical yield (30.3 g).

The purity of the compound was determined by HPLC and was 99.5%.

Example 3

0.1 mol of pyrmetazole hydrochloride (the compound was producedaccording to details stated in Example 31 of EP 0 005 129) weredissolved in 60 ml of water, then 60 ml of ethanol were added, the pHvalue of the solution was adjusted to greater than pH 7 with a 5 Nsodium hydroxide solution and a further 120 ml of water were added atroom temperature (25° C.), wherein the hydrates of the pyrmetazolecrystallised. The whitish crystalline product was separated, washed withwater and dried under a vacuum.

Yield: 90.2% relative to theoretical yield (29.5 g).

The purity of the compound was determined by HPLC and was 99.9%.

Example 4

Pyrmetazole, in the form of a solution in methylene chloride, was firstproduced according to Example 26 of EP 0 899 268. Methylene chloride wasremoved under a vacuum from such a solution, which contained 0.1 mol ofpyrmetazole. The residual oil was dissolved in 210 ml of ethanol andcaused to crystallise as the hydrate of pyrmetazole by the addition of630 ml of water. The whitish crystalline product was separated, washedwith water and dried under a vacuum.

Yield: 96% relative to theoretical yield (31.5 g).

The purity of the compound was determined by HPLC and was 99.8%.

1. A process for isolating crystals of an optionally substituted2-(2-pyridinyl)methylthio-1H-benzimidazole hydrate of formula I:

in which R¹, R² and R³, identical or different, denote hydrogen, a C1-C8alkyl, C3-C8 cycloalkyl, C2-C8 fluoroalkyl or C1-C8 alkoxy moiety, R⁴and R⁵, identical or different, denote hydrogen, a C1-C8 alkyl, C3-C8cycloalkyl, CH₂—C3-C8 cycloalkyl, C1-C8 alkoxycarbonyl, C1-C8 alkoxy,C1-C8 fluoroalkoxy, CF₃—, C2-C8 fluoroalkyl or C(O)O—C1-C8 alkyl moiety,and R⁶ denotes hydrogen or a C1-C2 alkyl moiety and x means 0.5-2, saidprocess comprising: a) providing a reaction medium comprising (i) thefree base of the structural formula:

wherein R¹-R⁶ have the meaning given above; and (ii) a water-soluble,organic solvent; b) at most partially removing the water-soluble,organic solvent present in the reaction medium; c) adding water to thereaction medium at a temperature of below 40° C. in quantities of atleast 55 wt. % of water, relative to the weight of the reaction medium,to form hydrates; d) separating the hydrates formed as crystals; and e)optionally purifying the crystals.
 2. A process according to claim 1,wherein the water is added in quantities of at least 70 wt. % relativeto the weight of the reaction medium.
 3. A process according to claim 1,wherein the water is added in quantities of up to 75 wt. % relative tothe weight of the reaction medium.
 4. A process according to claim 1,wherein the water is added at a temperature of 20-25° C.
 5. A processaccording to claim 1, wherein the free base in the reaction medium wasprepared by a process comprising reacting a thiol-compound of theformula II:

with a reactive pyridine compound of the formula III:

in presence of at least one base.
 6. A process according to claim 5,wherein the base is at least one member selected from the groupconsisting of sodium and potassium hydroxide.
 7. A process according toclaim 1, wherein the free base is initially dissolved in awater-miscible, organic solvent.
 8. A process according to claim 1,wherein the water-miscible, organic solvent is an aliphatic alcohol, oran aprotic solvent, or a ketone, or a mixture of at least two of thesesolvents.
 9. A process according to claim 1, wherein the crystals arepurified by washing with at least one of water and a solvent/watermixture.